Synonyms of Retinitis Pigmentosa

progressive pigmentary retinopathy

rod-cone dystrophy

RP

General Discussion

Retinitis pigmentosa (RP) comprises a large group of inherited vision disorders that cause progressive degeneration of the retina, the light sensitive membrane that coats the inside of the eyes. Peripheral (or side) vision gradually decreases and eventually is lost in most cases. Central vision is usually preserved until late in these conditions. Some forms of RP can be associated with deafness, obesity, kidney disease, and various other general health problems, including central nervous system and metabolic disorders, and occasionally chromosomal abnormalities.

Signs & Symptoms

RP usually begins as night or dim light visual impairment (that is, difficulty in seeing in dimly lit environments or at dusk, or adapting to, or recovering function in, dim light after being in bright light for any length of time). Typically, this is followed by the affected individual’s growing awareness of a loss of peripheral vision. Symptoms are more often noticed between the age 10 and 40, but earlier and later onset forms of RP exist. Characteristically, symptoms develop gradually over time. The sudden onset of these same symptoms should point to a different cause, such as an autoimmune process. Older people with sudden onset of these symptoms are especially at risk for experiencing them as the result of having cancer (so called paraneoplastic retinopathy, which often co-occurs with an optic nerve involvement as well).

The rate and extent of progression of visual loss in RP can vary. The way that peripheral vision is lost in RP has been especially well characterized by various authors. It has been reported in various studies that the most variable aspect is the age of onset of the symptoms. This can vary not only between families and between subtypes of RP, but also within families. However, after that, the rate and modality of progression tends to follow a fairly predictable and stereotyped exponential pattern. This pattern signifies that, during the first decade of symptomatic disease patients experience a slower rate of disease progression, which then accelerates during the subsequent two decades, to slow again during the remainder of life. When other members of a family are affected, the rates of progression are often similar within that family, but some degree of variability exists in this aspect of RP too.

Some patients with RP or related disorders present with complex manifestations affecting also other organs, termed “syndromes”. The most common associations of RP with general health (so called “systemic”) problems causing these more complex syndromes are hearing loss and obesity, and are reviewed under the “Related Syndromes” section of this review.

Causes

Retinitis pigmentosa is a group of hereditary progressive disorders that may be inherited as autosomal recessive, autosomal dominant or X-linked recessive traits. Maternally inherited variants of RP transmitted via the mitochondrial DNA can also exist.

About half of all RP cases are isolated (that is, they have no family history of the condition). RP may appear alone or in conjunction with one of several other rare disorders. Over 60 systemic disorders show some type of retinal involvement similar to RP.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22, and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome, and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many numbered bands. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

Autosomal dominant disorders occur when only a single copy of a gene carries a variant (mutation) that, alone, is sufficient and necessary for the appearance of the disease. In dominant disorders, the abnormal gene can be inherited from either parent, or can be the result of a new mutation (termed a “de novo” mutation) in the affected individual. The risk of passing the abnormal gene from an affected parent to offspring is 50% for each pregnancy, regardless of the sex of the parent or of the resulting child. However, in some forms of dominant diseases including some types of dominant RP, patients that inherit the mutated gene will not develop the disease, or will develop a very mild form of it, due to a phenomenon called incomplete penetrance. The RP11 gene (PRPF31) causing autosomal dominant RP is especially prone to doing this, which poses a significant diagnostic challenge. Children who did not inherit the gene variant that causes the autosomal dominant disorder in question, even if born of affected patients, cannot develop the disease.

Autosomal recessive disorders occur when an individual inherits mutations in the same gene from each parent. If an individual receives one normal gene and one gene for the disease (“mutated”), he or she will be a carrier of the disease, but usually will not show symptoms. The risk of two carrier parents both passing the defective gene and having an affected child is 25% with each pregnancy. The risk of having a child who is a carrier, like the parents, is 50% with each pregnancy. The chance of having a child who receives normal genes from both parents and is both healthy and genetically entirely normal for that particular trait is also 25%. The risk of manifesting an autosomal recessive disorder is normally the same for males and females. All children born of a person affected with an autosomal recessive condition will receive one copy of the defective gene from the affected parent. Therefore, they will be healthy carriers like the parents of the affected patient were. A child born of a patient affected with an autosomal recessive condition can be affected only if the affected parent mates with someone who is also a carrier of mutations in the same gene causing disease in the patient. If this happens, then the risk of having an affected child becomes 50%. If an affected person mates with another affected person with a disorder caused by mutations in the same gene, then their risk of having a child affected with that same genetic condition will be 100%, as long as the gene causing the disease in the two parents is the same.

Since most individuals carry a few abnormalities in their genes, parents who are close blood relatives (consanguineous) have a higher chance than do unrelated parents of both carrying the same abnormality in any given gene, which increases the risk of having children with an autosomal recessive genetic disorder. These children will typically carry the same exact change in both copies of their genes (homozygous). However, in most instances, autosomal recessive conditions arise by the serendipitous mating between two unaware healthy carriers, each typically carrying a distinct mutation in the same gene (compound heterozygous).

X-linked recessive genetic disorders are conditions caused by an abnormality in a gene on the X chromosome. Females have two X chromosomes; however, one of the X chromosomes is “turned off” or inactivated during development, a process termed “lyonization”, and all of the genes on that chromosome are inactivated. Lyonization is a random process, and varies from tissue to tissue; within tissues it can also vary from cell to cell. Females who have a disease gene present on one X chromosome are carriers of that disorder. As the result of the lyonization process, most carrier females have about 50% of the normal X and 50% of the mutant X expressed in each tissue, and usually display only milder symptoms of the disorder.

Because of the randomness of the lyonization process, exceptions to this rule exist, particularly if the inactivation of one copy of the X chromosome is significantly “skewed” in favor of one of the copies. If the normal copy prevails, then female carriers can be and remain completely asymptomatic. If the mutant copy prevails, then carrier females can be affected as severely as males. At times, the pattern and ratio of inactivation of the X chromosome will vary between eyes, whereby carriers can present with significantly asymmetric disease (for example, one eye affected severely, and the other much less so). This is not at all uncommon in XLRP carriers.

Unlike females, males have only one X chromosome. If a male inherits an X chromosome that contains a disease gene, he will develop the disease. A male with an X-linked disorder passes the disease gene to all of his daughters, and the daughters will be carriers. A male cannot pass an X-linked gene to his sons because the Y chromosome (not the X chromosome) is always passed to male offspring. A female carrier of an X-linked disorder has a 50% chance with each pregnancy of having a carrier daughter, a 50% chance of having a non-carrier daughter, a 50% chance of having a son affected with the disease, and a 50% chance of having an unaffected son.

In recent years, molecular genetics advances have impacted the understanding and the classification of hereditary retinal diseases perhaps more than any other group of eye diseases, with more than 210 distinct genes mapped (that is, their approximate location on one of the chromosomes has been identified) and over 170 cloned (that is, precisely identified, located, and mutation(s) that cause forms of RP found in them).

Affected Populations

RP as a group of vision disorders affects about 1 in 3,000 to 1 in 4,000 people in the world. This means that, with a population of nearly 314 million in the United States in mid-July 2012 (see < http://www.census.gov/> for continuous updates), about 78,500 to 105,000 people in the United States have RP or a related disorder. With a worldwide population presently estimated at over 7.05 billion, it can be estimated that approximately 1.77 to 2.35 million people around the world have one of these disorders. Excluding age-related macular degeneration and glaucoma, the genetic causes of which are complex and linked simultaneously to more than one gene (so called “polygenic” disorders), RP is the most common cause of inherited visual loss.

Related Disorders

Signs of the following disorders can be similar to RP. Comparisons may be useful for a differential diagnosis:

Leber’s congenital amaurosis (LCA) and early-onset RP (EORP) are special forms of RP characterized by the presence of severe symptoms from birth or shortly thereafter, respectively. This sub-group of RP forms is inherited in an autosomal recessive fashion, although also X-linked RP tends to have a significantly earlier onset than other forms of RP. When present from birth as in LCA, the visual deficit of affected children is typically recognized because of the coexistence of unsteadiness of the eyes known as nystagmus. Nystagmus is characterized by either fast-beating movements or by wandering movements of the eyeballs. The appearance of the back of the eye can be normal or near normal for several years, but testing of retinal function in response to flashes of light (the electroretinogram, or ERG) will invariably reveal the disease status in these patients. LCA patients often develop a deformation of the cornea causing high astigmatism up to a frank cone-shaped deformation of the cornea known as keratoconus. Prompt recognition of, and molecular genetic diagnostic testing for LCA is becoming increasingly important since three independent gene therapy trials have thus far demonstrated partial restoration of vision in one form of LCA linked to the RPE65 gene (see below). There are many different genes responsible for LCA and for recessive EORP. (For more information on this condition, choose “Leber congenital amaurosis” as your search term in the Rare Disease Database.)

Pericentral RP is a subtype of RP that is characterized by loss of side vision right around the center of a patient’s vision in the shape of a donut. This form of RP can be inherited in various ways (recessive, dominant, and sporadic, that is, without an uncertain mode of inheritance). Pericentral RP tends to have later onset than typical RP, causes far less loss of peripheral vision (in fact, the farthest portions of the field of vision in pericentral RP are rarely affected), it has been reported to have an overall slower progression rate than typical RP but, unlike RP, once it becomes symptomatic to patients, pericentral RP tends to encroach the center of the patients’ vision more rapidly and more severely than typical RP. As a result of this feature of the disease, patients with pericentral RP tend to experience a greater loss in visual acuity and central vision than peripheral vision, which is opposite to what seen in typical RP, and is more similar to what observed in “RP inversa”, more properly termed nowadays cone-rod dystrophy. By ERG criteria, pericentral RP tends to equally compromise rod and cone cells (the primary vision cells of the retina) or, at times, cone cells more than rod cells. The genes responsible for pericentral RP have not been identified yet, but research is ongoing to discover them.

A group of disorders that is often confused with RP is that linked to mutations, to date, to a single gene, known as NR2E3. This gene affects the development of progenitor retinal cells. Mutations in this gene lead to disorders that can present with distinct clinical pictures, known respectively as Goldmann-Favre vitreoretinal dystrophy, enhanced S-cone syndrome (ESCS), and clumped pigmentary retinal degeneration. These three conditions, all inherited as an autosomal recessive trait, share the feature of congenital night blindness and better than normal (or selectively better preserved) vision of the short wavelength-sensitive (blue, or S) cones, due to the erroneous development of rods into S-cones in the retina of affected patients. Unlike RP, these patients have slower disease progression rates, but are also prone to complications that RP patients do not typically incur, such as splitting of the retina at the macular and peripheral level (retinoschisis) and retinal detachments. The retinal changes affecting patients with this group of disorders vary in appearance from whitish flecks to coin-shaped areas of confluent pigmentation that is typically located underneath the retina and not within it as seen in RP.

Cone-rod dystrophy (CORD) is a term that identifies a group of disorders that can be inherited as autosomal recessive, autosomal dominant, X-linked recessive, or mitochondrial (maternally inherited) traits. Opposite to RP, CORD typically affects central and daytime vision much more severely than peripheral and night vision, hence the classical term “RP inversa” with which this family of conditions was also known. CORDs are, at least in part, genetically distinct from RP. However, depending on the mutations, certain genes expressed in both rods and cones can cause either RP or CORD (for example, the RDS/peripherin gene in dominant forms, the ABCA4 gene in recessive forms, and the RPGR gene in X-linked forms).

Choroideremia is a vision disorder inherited as an X-linked recessive trait characterized by extensive defects (atrophy) in the pigmented layer of cells underneath the retina, the retinal pigment epithelium, and of the capillaries of the underlying vascular layer, the choroids, called the choriocapillaris. Much like RP, the major symptoms of this disorder include a progressive loss of the peripheral field of vision and night blindness, which can start as early as during childhood and as late as young adulthood. It has been shown that, despite the extensive retinal pigment epithelium and choriocapillaris loss that can occur early on in the disease, the neuroretina above areas of atrophy of these other tissues can remain at least partially intact and, therefore, partially functioning for an extended period of time, thereby explaining why, often times, the changes seen at the back of the eye of affected males appear more severe than the actual degree of visual loss experienced by the patients. Unlike RP, patients with choroideremia do not typically develop bone spicule-like pigmentary deposits in the retina, but rather scattered patches of irregularly shaped hyperpigmentation underneath the retina. The overall prognosis of choroideremia appears to be, on average, better than that of RP and XLRP in particular, but severe vision loss has been reported in choroideremia as well.

With very few exceptions, choroideremia affects only males. Unlike females carriers of X-linked RP, who commonly experience some sign of the disease however mild or late-onset they may be, female carriers of choroideremia only sometimes have symptoms, although a few will complain about dim light or night vision late in life. Despite the relative lack of symptoms experienced by female carriers, they can usually be identified as such by characteristic pigment mottling in the retina after the pupils of the eye has been dilated.

Related Syndromes

The most common associations of RP with general health (so called “systemic”) problems causing more complex disorders known as “syndromes” are hearing loss and obesity.

Some individuals with RP can be born deaf (Usher syndrome type I or infantile-onset Refsum disease), or hearing-impaired (Usher syndrome type II), or can become hearing impaired (Usher syndrome type III or adult-onset Refsum disease). A more rare form of hearing-related syndrome that can present also with an RP-like retinopathy is Wolfram syndrome, but optic atrophy and diabetes mellitus are the most manifestations of this disorder. Hearing impairment of various degrees of severity and type can be present also in RP variants caused by changes in mitochondrial DNA. The type of deafness/hearing loss presented by patients with these conditions is termed sensorineural, that is, linked to malfunction or progressive degeneration of the hearing nerves and nervous structures, which are much like the type of visual loss that occurs at the level of the retina.

Usher syndrome is a group of inherited disorders characterized by RP and hearing impairment. Usher syndrome accounts for about 50% of all deaf-blinding disorders. The exact prevalence (frequency) of Usher syndrome in the population is not precisely known, but it has been estimated to affect 1:10,000 to 1:20,000 people. Usher syndrome is, for the most part, genetically distinct from non-syndromic forms of RP, although some cases of simple RP (that is, without hearing loss) in association to mutations in the USH2A gene have been reported. There are three major types of Usher syndrome, distinguished by the severity and the age of onset of the hearing features. Type I is characterized by congenital, non-progressive, profound hearing loss. Type II is characterized by congenital, non-progressive, mild to moderate hearing loss, whereby speech is much less affected. Type III, which is more rare, is characterized by progressive, late-onset (post-verbal) hearing loss; speech is typically not affected. Although three main types of Usher syndrome are recognized clinically, many more genes accounting for these clinical subtypes exist. To date, 10 genes have been mapped (six for Usher syndrome type I, USH1B-G, three for type II, USH2A-C, and one for type III, USH3A), eight of which cloned. The USH1A gene on chromosome 14q has been withdrawn. A type IV Usher syndrome with X-linked recessive inheritance was suspected to exist in the past, but this has now been shown to be a pseudo-Usher syndrome linked to mutations affecting the RRC1-like domain of the RPGR gene, a common cause of X-linked RP, which is also expressed in the epithelial lining of the respiratory tract and in the inner ear. This variant is also associated with recurrent upper respiratory tract infections (especially otitis and sinusitis) and immotile cilia-like symptoms.

Refsum syndrome is a slowly progressive disorder of fat (lipid) metabolism inherited as an autosomal recessive trait that is characterized by the accumulation of phytanic acid in the blood and tissues. The main features of this disorder in its more common, adult-onset form are RP, peripheral neuropathy (typically numbness and weakness), impaired ability to coordinate movement (ataxia), and late-onset, progressive hearing loss. As such, unlike Usher syndrome type I and II but similar to Usher syndrome type III, speech is typically not affected in Refsum disease. Infantile-onset forms, though, are more severe, and include other features such as congenital deafness and failure to thrive. Prompt recognition of this disorder is important because it can be either kept from worsening or reversed with a high-calorie diet devoid of foods rich in phytanic acid (such as butter and animal fat) combined with plasmapheresis. Demonstration of elevated levels of circulating phytanic acid is diagnostic. To date, there are five distinct genes that can cause Refsum disease, two causing the adult-onset form and three that cause the infantile-onset form, which are all linked to defective function of peroxisomes.

Obesity syndromes are rarer than the ones associated with hearing loss. Of them, the most common form of obesity syndrome is Bardet-Biedl syndrome (BBS). The BBS spectrum of clinical manifestations includes, in addition to RP, obesity, abnormality of the extremities such as more than the normal number of fingers and/or toes (polydactyly), fused digits (syndactyly), or shorter than normal digits (brachydactyly), and underdevelopment of the testes and small external genitalia (more apparent in males), kidney anomalies at times as severe as kidney failure, impairment of smell function (typically revealed only by formal testing), dental abnormalities, vertebral abnormalities, behavioral abnormalities, and in some cases intellectual disability. Some individuals also have asthma, diabetes, and elevated lipid profiles.

BBS is estimated to affect less than 1:100,000 people, although in populations with high degree of consanguinity (inbreeding) the incidence can be significantly higher (e.g., certain Bedouin tribes in which the first few BBS genes were mapped). Despite its rarity, BBS is markedly heterogeneous from a genetic point of view, with 17 distinct genes implicated in causing this disorder to date. Most BBS genes share a role in the function of cilia, which are present, for example, in the retina and kidneys, or that of functioning as chaperonins (e.g., BBS6, BBS10, and BBS12). BBS1 accounts for the majority of cases of BBS, followed by BBS10. The genetic overlap between BBS and other conditions has recently emerged, with mutations in CEP290 (also known as or NPHP6), which is the cause of LCA, Senior-Loken syndrome, Joubert syndrome, and Meckel syndrome type 4, being associated also with BBS (BBS14 gene). It has also been suggested that, unlike most other conditions, more than two mutations in more than one gene may be necessary to cause BBS (triallelic or polyallelic inheritance). However, this phenomenon has not been verified as necessary in all studies. Most certainly, though, the convergence of the BBS genes at certain subcellular levels, such as the cilia, creates the premises for significant epistatic effects, i.e., an increase (or decrease) in severity of the disease, caused by the main mutations (inherited in a classical Mendelian autosomal recessive mode), exerted on these mutations by mutations (or polymorphisms) in either other BBS genes or in additional ones relevant to the function of the subcellular structure in question in the case of BBS, the cilium.

Despite the similarity in symptoms between RP and BBS, BBS patients often have late-onset retinal changes, whereby the diagnosis of BBS is often delayed until an ERG is performed, showing invariably profound retinal disease. Similar to LCA, development of nystagmus and high astigmatism are also common in BBS.

Alström syndrome (ALMS) is another rare obesity syndrome inherited as an autosomal recessive trait, characterized by CORD, obesity, dilated cardiomyopathy (typically infantile in onset) and subsequent development of diabetes mellitus, sensorineural, post-verbal hearing loss, and kidney disease. Unlike RP patients and most BBS patients, but similar to LCA, ALMS patients are typically born with nystagmus. However, ALMS patients also complain primarily of light aversion and far less so of night blindness. ALMS patients do not usually have polydactyly, syndactyly, or brachydactyly as seen in BBS. The gene responsible for ALMS is ALMS1. Although distinct from the BBS genes, ALMS1 is also involved in ciliary function, explaining the similarity between BBS and ALMS and establishing an additional link between ciliary dysfunction and syndromes characterized by obesity and kidney dysfunction. Consistent with this, partial overlap in the manifestations of the two syndromes has been reported, with BBS patients with documented BBS gene mutations exhibiting ALMS-like features such as hearing loss and diabetes.

Senior-Loken syndrome (SLSN) is a variant of LCA inherited as an autosomal recessive trait in which, similar to BBS and ALMS, there is multi-cystic involvement of the kidneys that can evolve in serious damage to kidney function (nephronophthisis), which carries marked morbidity. Unlike BBS and ALMS, though, SLSN patients are not obese and do not have abnormalities of the digits. Additional features that can often be observed in SLSN patients are sensorineural hearing loss and cone-shaped deformity of long bone epiphyses. Less commonly, SLSN patients can also present with liver fibrosis, cerebellar ataxia, diabetes insipidus and, at the ocular level, with congenital cataracts and keratoconus. Although SLSN is rarer than LCA and BBS, due to the severity of the renal involvement, prompt recognition of this disorder has important diagnostic and prognostic implications.

Five distinct genes responsible for SLSN have been cloned to date, all of which are part of the family of the nephrocystins, important proteins expressed in the kidney as well as in the retina and other organs and tissues characterized by the presence of cilia. Therefore, also SLSN is a member of the emerging group of ciliopathies. As noted above in the BBS section, CEP290 (also known as NPHP6), which is responsible for a form of LCA, is also one of the genes responsible for one type of SLSN as well as BBS and other clinically distinct but clearly allelic conditions.

Lastly, a rare RP syndrome is abetalipoproteinemia, or Bassen-Kornzweig syndrome, a disorder inherited as an autosomal recessive trait characterized by the presence of misshapen red blood cells (acanthocytosis) in the circulating blood. This disorder usually begins in the first year of life and is characterized by a progressive inability to coordinate movement (ataxia), RP, the malabsorption of fat in the digestive system with fatty, greasy stools (steatorrhea) and low serum cholesterol since childhood (celiac syndrome). Serum beta lipoprotein is absent as a result of defective function in the microsomal triglyceride transfer protein, encoded for by the MTP gene. The aforementioned clinical and laboratory features allow for differentiation of this condition from Refsum disease. Despite its rarity, awareness of the characteristics abetalipoproteinemia is very important because the syndrome is responsive to vitamin A, E and K supplementation. Therefore, as in Refsum disease, early diagnosis of abetalipoproteinemia is crucial.

Diagnosis

RP is diagnosed by electroretinography (ERG) showing progressive loss in photoreceptor function and visual field testing. Molecular genetic testing for mutations in many of the genes associated with RP is available to confirm the diagnosis.

Standard Therapies

Treatment

Dietary Supplements

The treatment regimen for patients with RP has evolved during the last two decades. A six-year study of patients aged 18 through 49 years conducted at Harvard Medical School with the support of the National Eye Institute and the Foundation Fighting Blindness, showed that those who supplemented their regular diets with 15,000 IU (international units) daily of vitamin A palmitate had a slower decline of retinal function than those who received only trace amounts. It must be noted that vitamin A palmitate is the specific form of vitamin A that was used in this trial. Beta-carotene needs to be metabolized by the liver and broken down into vitamin A before it can be utilized by the body. The rate of absorption and metabolism of beta-carotene varies greatly between individuals and also within the same individual depending on other factors. Beta-carotene, therefore, although a precursor of vitamin A, is not a suitable substitute for vitamin A palmitate. The study results also suggested that taking 400 IU daily of vitamin E supplementation actually hastened the progression of retinal disease, whereby RP patients are recommended against taking vitamin E supplements in addition to what is provided by a regular, balanced diet. This means that virtually all RP patients should not be on generic multivitamins, which are rich in both beta-carotene (but not vitamin A palmitate) and vitamin E, as well as a number of other supplements the effects of which on RP progression are not presently known.

Long-term supplementation with these regimens of vitamin A palmitate appears to be safe, although older patients should be aware that there is some evidence (although not univocal) that vitamin A supplements may promote further bone density loss, worsen osteoporosis and, therefore, increase the risk of hip fractures. In these cases, it may be wise to obtain a baseline bone density scan and, in the presence of existing osteoporosis, treat appropriately the underlying disorder before starting vitamin A supplements and monitor closely the bone density profiles thereafter. In addition, since an adverse interaction between smoking and beta-carotene has been documented, whereby smokers of such supplements have an increased risk of lung cancer, smokers should not be on vitamin A- or beta-carotene-containing supplements, and smokers with RP should not start vitamin A palmitate supplements until successful completion of a smoking cessation program. Monitoring liver function very 1-2 years while on vitamin A palmitate supplements is advisable even in the absence of liver disease. RP patients with liver disease may not be able to tolerate the full dose of recommended vitamin A supplement, and decision on use and dosage should be made individually by treating physicians.

It should also be noted that more is not better. Because long-term high-dose vitamin A supplementation (e.g., exceeding 20,000 IU) may cause certain adverse effects such as liver disease, patients should not undertake such high supplementation regimens unless so recommended by their treating physician and unless regularly monitored for liver function status when taking such supplementation.

Supplementation has not been formally studied in children. Therefore, the exact dosage to be given to children with RP is not known. However, one can assume the dosage of 15,000 IUs to be intended for an adult of average body weight of 80 Kg (approx. 175 lb). From these values, the 15,000 IUs daily dose could then be extrapolated to 188 IUs per Kg of body weight (or about 86 IUs per lb of body weight) and adjusted empirically accordingly used the 2000 growth charts freely available at the CDC website. Furthermore, vitamin A use can cause malformations of the fetus during pregnancy. The highest risks have been identified in women taking more than 10,000 IUs of vitamin A daily (identified as a threshold level) and especially those taking high supplements during the first 7 weeks of gestation. Above this dosage, the risk for certain specific malformations was estimated at about 1 in 57 (hence, about 1.8%). Therefore, women of childbearing age should be careful while on vitamin A supplements and either avoid becoming pregnant while on the 15,000 IU daily supplements, or monitor the frequency of their menstrual cycles while on supplementation and interrupt or reduce promptly vitamin A supplements as soon as they become aware of being pregnant. Women intending to become pregnant should consider reducing supplementation to less than 10,000 IUs daily, or perhaps discontinuing altogether the vitamin A supplements during period of active attempts to conceive. However, it does not appear that vitamin A use during pregnancy should be completely avoided. The use, and dose, of any supplements during or around pregnancy should be carefully discussed by individual patients with their doctors.

Further studies by the same group at Harvard have shown that additional, short-term benefits can be obtained by treating naïve RP patients with 15,000 IU of daily vitamin A palmitate in combination with 1,200 mg of docosahexaenoic acid (DHA), an omega-3 fatty acid that is a key component of fish oil. In addition, current treatment recommendations include an omega-3 rich fish diet for those already on vitamin A supplements, since subgroup analyses suggest potentially harmful effects of initiating DHA supplementation while already on the vitamin A supplements.

Additional studies from the same group at Harvard have more recently reported a reduction in the rate of visual field sensitivity loss in RP patients that took 12mg of daily lutein added to the previously studied 15,000 IU vitamin A supplementation regimen compared to those on vitamin A alone.

Patients with less common disorders that may be associated with RP were not evaluated in these supplementation studies. In addition, certain patients were not included, such as patients with severely advanced RP. Thus, based on the results of these studies, precise recommendations cannot be made regarding vitamin A supplementation for these patients.

Treatment of Cystoid Macular Edema

A common complication of RP is the formation of small pockets of fluid in the centermost part of the retina, called cystoid macular edema, or CME. CME can cause significant reduction in central visual acuity, as well as blurred vision, and glare. If untreated, further degenerative changes in the retinal tissue will ultimately occur, and the development of a macular hole by rupture of a central larger cyst can also occur. With the current imaging techniques available in the clinical setting to ophthalmologists and other eye care providers, detection of CME changes has become much easier and much more precise. A study with such techniques estimated the frequency of cystic macular changes consistent with CME to be 38% in at least one eye and 27% in both eyes of RP patients. This complication can be successfully treated with oral (tablets) or topical (eye drops) medications of the family of the so-called carbonic anhydrase inhibitors (CAIs), such as acetazolamide or metazolamide (tablets) and dorzalamide or brinzolamide (topical eye drops). While not all patients will respond to these treatments, these medications have been shown to diminish and often eliminate the cystic changes in the retina of RP patients, improving visual acuity in the short term and improving the overall functional prognosis over the long term. Some side effects can result from use of these medications, but most of them can be managed. Patients allergic to sulfonamides should not be taking CAIs. CAIs have been shown to be effective in reducing or resolving cystic changes also in patients with similar findings due a different problem, called macular retinoschisis, as it is seen in patients with ESCS or another hereditary vitreo-retinal disorder, called X-linked retinoschisis.

Since an inflammatory component to CME is also likely, and an increased frequency of certain antibodies in the bloodstream of RP patients with CME has been reported, corticosteroids utilized off-label and injected around (that is, periocularly) or directly inside the eye ball (that is, intravitreally) of RP patients with CME have also been tried in some patients that do not respond to CAIs, and variable success has been reported. However, the intravitreal use of these medications increase the risk of other complications, such as glaucoma or cataract, and a small but serious risk of infection inside the eye ball (endophthalmitis) exists with all intravitreal injections. Therefore, this approach should be used only as a second line treatment in RP until formal trials of the efficacy of these treatments are conducted. Periocular injections pose a much lower risk of glaucoma and cataracts, and do not pose a risk of endophthalmitis. A new formulation of one such medication specifically designed for intravitreal injection has recently become available, but has yet to be tried in patients with RP.

Supportive Measures

For individuals with RP, low-vision aids and other assistive devices may be of benefit as vision worsens. In addition, genetic counseling will be of benefit for affected individuals and their families. Although a study of light deprivation in RP was conducted many years ago without benefit, the concern that light damage may play a role in worsening retinal degeneration in some forms of RP remains. This concern is in part supported by recent evidence that, in a dog naturally affected with RP resulting from a mutation in the rhodopsin (RHO) gene, evidence for light-induced worsening of the disease has been obtained. Therefore, to err on the side of caution, use of sunglasses in the outdoors and avoiding undue and unnecessary exposure to excessive amounts of light is generally recommended to all RP patients.

Investigational Therapies

Gene Therapy

After many years of successful studies in animals affected by RP, an exciting new development in the field of RP research is the outcome of three independent human clinical trials of gene therapy for LCA caused by RPE65 gene mutations. Participants in these trials have been treated with one or more injections under the retina of specially engineered viral particles containing “good” copies of the RPE65 gene for delivery to the diseased cells of affected patients. All three of these milestone studies, using different means of assessment of visual function, have demonstrated improved vision in virtually all patients. These very encouraging studies open the possibility that correction of the underlying genetic defect inside the retina via gene therapy may be used to treat most, if not all, forms of RP and related disorders. However, additional studies are required to verify this possibility and to identify the appropriate “therapeutic window” within which efficacy of gene therapy can be achieved and maximized.

Very recent, encouraging studies of gene therapy in a naturally occurring canine model of X-linked RP linked to mutations in the RPGR gene have laid the groundwork for human gene therapy trials also of this form of RP. Other human, Phase I/II gene therapy trials are presently ongoing for choroideremia, which is also X-linked (ClinicalTrials.gov identifier: NCT01461213), for ABCA4-linked recessive Stargardt macular dystrophy (ClinicalTrials.gov identifier: NCT01367444), and for Usher syndrome type IB linked to mutations in the MYO7A gene (ClinicalTrials.gov identifier: NCT01505062). More such trials for other conditions are expected in the next few years.

Gene therapy is possible only in patients whose disease genetic cause has been discovered; additionally, gene therapy for disorders other than a recessive one like LCA has yet to be tried in humans. Presently, this treatment is not possible for all RP patients, and for some it may become possible only in quite a few years from now. Therefore, other treatment strategies remain important to use and pursue.

Treatment strategies that can be used as an alternative to, or in addition, to, gene therapy can be gene-independent or gene-specific ones.

Gene-independent therapies are aimed at providing benefit to retinal health across the board, regardless of the genetic cause. Nutritional treatments like vitamin A palmitate and lutein fall in this category. Other such examples include:

CNTF. One such treatment that is presently being studied in clinical trials of RP is a growth factor, known as ciliary neurotrophic factor, or CNTF, delivered to the retina via tiny porous capsules in which live cells engineered to produce a specific amount of CNTF are trapped and held in place by special scaffolding. The specially designed porous nature of the capsule allows nutrients to enter while also allowing CNTF to leave the capsule, for slow release inside the vitreous cavity of the eye ball and diffusion to the retina. A Phase I safety trial, which not only showed excellent safety but also suggested possible improvements in some aspects of visual function in some of the treated eyes, has been successfully completed.

CNTF Phase II/III clinical trials with this special proprietary device at a dozen different sites across the United States have been recently completed. Two trials of RP have been recently completed: the CNTF3 trial aimed at assessing the efficacy of the CNTF-releasing implants on visual acuity in advanced RP one year after the implants had been placed in the eye; the CNTF4 trial was a 2-year trial aimed at assessing the efficacy of the implants on visual sensitivity across the central visual field in patients with earlier stages of RP. Additionally, a CNTF2 trial was conducted on patients with the dry form of age-related macular degeneration (dry AMD or “geographic atrophy”). These Phase II/III trials confirmed the safety of the implanted devices, but did not achieve their therapeutic objectives, whereby treatment with CNTF-releasing implants cannot be considered a suitable treatment for RP or dry AMD at this time. However, some encouraging post-trial sub-analyses indicated that the implants did exert some effect. Retinal thickness was consistently higher in treated eyes than the fellow eyes that did not receive the implants across all three trials. Also, studies of macular cones by means of an emerging imaging technique based on the principle of “adaptive optics” suggested that macular cones may have been better preserved in eyes that received the implants than the fellow eyes. Neither of these were primary outcome measures for the CNTF trials, whereby these reasons were insufficient to deem the implants effective by FDA standards. Long-term follow up of treated patients is still in progress to determine if a favorable effect of the implants may be detected at later time points. Whether CNTF will be reconsidered for investigation in RP, AMD and related diseases in the future is not presently known. The CNTF trials did show, however, that the device is safe and, therefore, could be used with different treatments in the future, and suggested that inclusion of imaging outcomes in future trials may be able to capture response to treatment better than global functional outcomes. It is still somewhat uncertain how to best relate imaging outcomes to standard and widely accepted visual function outcomes such as visual acuity and visual fields.

Argus II. A Phase II clinical trial entitled, “Argus” II Retinal Stimulation System Feasibility Protocol to test the safety and efficacy in restoring visual acuity in patients with very advanced RP (with a residue of bare light perception or less in each eye) was recently completed. The Argus II artificial retina implant was developed by Second Sight in conjunction with the Artificial Retina Project Consortium sponsored by the Department of Energy. This trial was conducted at several sites in the US, Enrollment in this trial is presently completed (ClinicalTrials.gov identifier: NCTNCT00407602). Preliminary results have been reported and appear very encouraging, although technological development of the implants and long-term monitoring of the patients who received the implants (ClinicalTrials.gov identifier: NCT01490827) remain in progress.

Tissue Transplantation. A Phase II trial of fetal retinal tissue transplantation into the eyes of patients with advanced RP has been completed (ClinicalTrials.gov identifier: NCT00345917). Interim results after one year of follow up in one of the participating subjects have been reported, suggesting no rejection of the transplanted tissue and progressive and sustained improvement of visual acuity from 20/800 at baseline to 20/160 at one year. Enrollment in this study, which aimed at recruiting 10 subjects, has been recently completed and results of this experimental approach remain pending.

Stem cells. Trials of this promising treatment option are not yet being performed for RP. However, some trials that utilize embryonic stem cell-derived pigment epithelial cells are ongoing for Stargardt macular dystrophy (ClinicalTrials.gov identifier: NCT01505062 and NCT01345006). Results are expected within the next few years.

Supplementation. Another ongoing trial is a specific one of DHA supplementation in children and young adults with X-linked RP, which is being conducted at the Retina Foundation of the Southwest (ClinicalTrials.gov identifier: NCT00100230). This trial is testing the potential benefits of a higher dose of DHA than that previously tested on the same type of RP, with results trending toward possible efficacy but inconclusive as to whether DHA alone would be effective in slowing down disease progression. Results of this trial will become known within the next few years.

Posterior Segment Drug Delivery Systems. Lastly, one more Phase I/II trial that is presently ongoing and open for enrollment is that of a micro-implant, called Posterior Segment Drug Delivery System, that is injected inside the vitreal chamber of the eye ball and that is designed to release over time a medication, called brimonidine tartrate (ClinicalTrials.gov identifier: NCT00661479). Three different dosages of this medication are being tested in one eye of patients with RP (at a single study site in the United States and at three sites in Europe). This medication has existed on the market as an eye drop to lower eye pressure in patients with glaucoma for numerous years. Several lines of evidence suggested that brimonidine tartrate has neuroprotective potential on the optic nerve. Additional in vitro studies demonstrated the strong neuroprotective potential of this specific drug on degenerating rod and cone cells in the retina. These findings added to other studies on related compounds, which also had shown significant retinal neuroprotective potential. Despite the significant potential displayed by brimonidine tartrate, difficulties in delivering an adequate dose to the retina via the use of simple eye drops, combined with a relatively high frequency of intolerance to topical administration, limited the applicability of this potential treatment. The new delivery strategy that has been developed by the sponsoring company to this trial opens the door to a reappraisal of this treatment strategy and its possible utilization to afford neuroprotection to the degenerating retina of RP patients. Results of this Phase I/II trial are pending.

Gene-specific therapies. Like for gene therapy, to benefit from these treatments, patients need to know the specific genetic cause of their individual disease. Molecular genetic diagnostic testing is nowadays available for most if not all genes. Therefore, when possible, testing under the guidance of an experienced ophthalmic geneticist is strongly recommended for all patients, as this can not only provide far greater diagnostic accuracy, but also open the door to a variety of emerging and forthcoming treatment options.

Other than gene therapy itself, treatments falling in this category are directed at genetically defined groups of patients that are more likely to respond to a certain treatment depending on certain genetic characteristics. Examples of this include:

a) Patients that share a certain type of mutation: for example, nonsense mutations that lead to truncation of the protein produced by the gene in question can be in theory overcome by certain drugs. Such type of drug is being currently studied in a pulmonary disease known as cystic fibrosis. Retinal disorders in which nonsense mutations are particularly common include choroideremia and, to a lesser extent, certain forms of X-linked RP, but nonsense mutations have been reported for nearly every form of RP and related disorders. Therefore, if such treatments were to be proven safe and effective, there is a possibility that patients with any form of RP may benefit from such drugs so long as they have their diseases harbored by this category of mutations.

b) Patients with mutations in different genes but that result in the same net molecular effect: for example, mutations that result in overall misfolding of the encoded protein could be partially overcome by molecules that exert a chaperone effect. One such type of drugs may be valproic acid (VPA), a drug long known as an effective medication for seizure disorders. A study on misfolded molecules of rhodopsin, which is a common cause of dominant RP, showed that VPA is capable of improving the folding of mutated molecules responsible for dominant RP. This suggests that patients with genetic mutations affecting the folding of the encoded protein may benefit from VPA and, since misfolding is a common problem in dominant RP and anecdotal, open-label evidence suggests that VPA may be able to improve visual field size in dominant RP, a Phase II trial of VPA is presently being conducted on patients with dominant RP (ClinicalTrials.gov identifier: NCT01233609) and will have a follow up of at least one year. The exact VPA dose that may be effective in RP, if any, is not presently known, and VPA can have serious side effects, especially in pregnant women. Therefore, RP patients are strongly cautioned to await the outcome of this double-masked, randomized, placebo-controlled multi-center trial before requesting VPA prescriptions of any dosing from physicians.

c) Patients sharing mutations in the same gene leading to same, disease-causing downstream defect: for example, diseases in which a certain carotenoid molecule indispensable for vision cannot be recycled because of a defect in the enzyme needed to complete the recycling process could be overcome by treating patients with a synthetic version of the needed carotenoid that bypasses the enzymatic defect. One such example is (an ongoing trial of) a synthetic derivative of vitamin A, called compound QLT091001. The enzyme produced by the LRAT gene is necessary for the recycling of specially shaped molecules of vitamin A that rods in the retina need for night vision. When this recycling process is disrupted due to mutations in the LRAT gene, patients experience night vision problems and develop a form of recessive RP. Oral administration of QLT091001 on an experimental, open-label basis in patients with RP resulting from LRAT mutations has been reported to improve significantly their visual field. For this reason, two trials of QLT091001 are presently ongoing (ClinicalTrials.gov identifiers: NCT01014052 and NCT01521793).

In addition, the Foundation Fighting Blindness lists a brief summary of clinical trials conducted for RP and other diseases on their website (http://www.fightblindness.org).

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222

TTY: (866) 411-1010

Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:

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